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A Stricker-Krongrad

Publications and source records attributed to A Stricker-Krongrad.

At least 19 recordsLinked to original sources
PubMed2001

Opposite regulation of hypothalamic orexin and neuropeptide Y receptors and peptide expressions in obese Zucker rats.

Many hyothalamic neuropeptides are involved in the regulation of food intake and body weight. The orexins (OX) which are synthesized in the lateral hypothalamus are among the most recently characterized whereas neuropeptide Y (NPY) belongs to a group of "older" peptides extensively studied for their effects on feeding behavior. Both stimulate food ingestion in rodents. In this experiment, we measured the expressions of these peptides as well as of their receptors (OX1-R and OX2-R, Y1 and Y5) in the hypothalamus of obese hyperphagic and lean Zucker rats by real-time RT-PCR using the TaqMan apparatus. NPY mRNA expression in the obese rats was significantly increased by a factor of 10 (P < 0.002) whereas expressions of the Y1 and Y5 receptors were decreased by 25% (P < 0.01) and 50% (P < 0.002), respectively. Their prepro-orexin mRNA expression was more than twofold decreased (P < 0.01) and expressions of their OX receptors 1 and 2 mRNA were five- and fourfold increased (P < 0.05), respectively. An inverse phenomenon was therefore noted between the two peptides: for NPY, increased levels and downregulation of receptors; and for OX, diminished levels with upregulation of receptors. The reasons for these changes might be linked to the absence of leptin signaling as similar profiles are found in the ob/ob mice. For orexins at least, other factors such as hyperglycemia might be involved. Based on anatomical considerations, a direct effect of NPY or of other brain peptides such as CRH cannot be excluded. We conclude that the diminution in the OX tone might participate in a counterregulatory system necessary to limit the noxious effects of NPY on food intake and body weight.

Animals↗
PubMed2001

Central and peripheral dysregulation of melanin-concentrating hormone in obese Zucker rats.

Melanin concentrating hormone (MCH) is a peptide synthesized in the lateral hypothalamus which stimulates food ingestion and leptin secretion in rodents. In this experiment, we measured the expressions of MCH as well as of its receptor (SLC-1) in the hypothalamus of obese hyperphagic and lean Zucker rats by quantitative real time RT-PCR. MCH mRNA expression in the obese rats was significantly increased by a factor of five (P<0.01) whereas expression of SLC-1 was decreased by more than 50% (P<0.05). Circulating levels of leptin and MCH were increased in the plasma of obese Zucker rats when compared to lean rats (38-fold and 1.7-fold, respectively, P<0.001 and P<0.01). However, individual MCH levels were not directly correlated to leptin levels in the lean (functional leptin receptor) or in the obese (non-functional leptin receptor) Zucker rats. These results indicate that the absence of leptin signaling in rats is associated with an increased hypothalamic expression and circulating release of MCH, contributing to their obesity syndrome.

Animals↗
PubMed2000

Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice.

Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.

Adipose Tissue↗
PubMed2000

Identification of leptin-induced transcripts in the mouse hypothalamus.

Long-form leptin receptor (OB-R(L)) is a signal-transducing member of the cytokine receptor superfamily that is essential for mediating the effects of leptin on mammalian body weight homeostasis. At present, the range of transcriptional targets responsive to OB-R(L) activation, and consequently, the likely mediators of leptin action, remain undefined. In this report, we have used cDNA subtractive hybridization to identify transcripts induced by leptin in immortalized hypothalamic neurons expressing OB-R(L). Differential expression of the identified transcripts in these cells was confirmed by both array technology and Northern blotting. In situ hybridization studies indicate that these transcripts are expressed in the mouse central nervous system, including nuclei of the hypothalamus that coexpress OB-R(L). Comparative in situ analysis of slices of hypothalami generated from control and leptin-injected ob/ob mice demonstrates that a subset of the identified transcripts is induced in vivo after leptin injection. The potential role of the proteins encoded by these transcripts in mediating the effects of leptin on body weight and energy homeostasis are discussed.

Adenoviridae↗
PubMed1999

A peptide leptin antagonist reduces food intake in rodents.

OBJECTIVE: The purpose of the present study was to investigate the continuing validity of the hypothesis that leptin is a physiologically important regulator of food intake, using the human leptin mutant R128Q leptin. DESIGN: In a cellular proliferation assay, based on BAF-3 cells transfected with the murine ObRb receptor, R128Q leptin was shown to be devoid of agonistic activity and to competitively inhibit the proliferative effects of leptin. To determine whether R128Q leptin was also an antagonist of leptin in vivo, the leptin mutant was injected intracerebroventricularly (i.c.v.) into rats in the absence and presence of leptin. R128Q was also injected intraperitoneally (i.p.) into ob/ob and into db/db mice expressing, respectively, either normal or defective ObRb receptors. RESULTS: R128Q was shown to be a competitive antagonist of leptin induced cellular proliferation in vitro. Surprisingly, in vivo R128Q leptin produced a strong dose-dependent decrease in food intake, and was only slightly less potent than leptin itself. In fasted rats, the inhibitory effects of leptin and R128Q leptin (i.c.v.) on post-fast refeeding were additive. Finally, R128Q leptin produced the same inhibition of food intake as leptin when injected i.p. in ob/ob mice and, like leptin, was inactive after i.p. injection to db/db mice. CONCLUSION: R128Q leptin is a leptin agonist in vivo, but behaves as an antagonist against leptin induced proliferation in vitro. The data demonstrate that the human leptin mutant R128Q leptin is not a suitable tool for investigating the physiological actions of leptin.

Animals↗
PubMed1999

Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat.

It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.

Animals↗
PubMed1998

Independent feeding and metabolic actions of orexins in mice.

Orexin-A and orexin-B (OX peptides) are two putative products of a newly discovered secreted protein encoded by a mRNA restricted to neuronal cell bodies of the lateral hypothalamus (LH). Because the activation of the LH can induce changes in energy balance, we wanted to investigate the actions of OX peptides on energy metabolism in mice. We injected male C57BL/6J mice with different doses (1, 3, and 10 nmol) of orexin-A and orexin-B into the third ventricle (i3vt). A single i3vt injection of orexin-A 3 h into the light period slightly stimulated feeding at the lowest dose only over the following 4 h (11 +/- 09 mg/mouse vs 80 +/- 13 mg/mouse, p < 0.05). Orexin-B showed no effects at any dose. We therefore investigated the effects of 3 nmol orexin-A on energy utilization using indirect calorimetry. Single i3vt injection 3 h after light on, or just before dark onset, or in 4-h fasted mice resulted in increases in the metabolic rate. These effects were associated with decreases or increases in the respiratory quotient regarding the time of injection or the underlying metabolic state of the mice. The present findings provide direct evidence that OX peptides are more likely to be involved in the control of energy metabolism than of food intake in mice.

Animals↗
PubMed1998

Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor.

The new neuropeptide Y (NPY) Y5 receptor antagonist CGP 71683A displayed high affinity for the cloned rat NPY Y5 subtype, but > 1, 000-fold lower affinity for the cloned rat NPY Y1, Y2, and Y4 subtypes. In LMTK cells transfected with the human NPY Y5 receptor, CGP 71683A was without intrinsic activity and antagonized NPY-induced Ca2+ transients. CGP 71683A was given intraperitoneally (dose range 1-100 mg/kg) to a series of animal models of high hypothalamic NPY levels. In lean satiated rats CGP 71683A significantly antagonized the increase in food intake induced by intracerebroventricular injection of NPY. In 24-h fasted and streptozotocin diabetic rats CGP 71683A dose-dependently inhibited food intake. During the dark phase, CGP 71683A dose-dependently inhibited food intake in free-feeding lean rats without affecting the normal pattern of food intake or inducing taste aversion. In free-feeding lean rats, intraperitoneal administration of CGP 71683A for 28 d inhibited food intake dose-dependently with a maximum reduction observed on days 3 and 4. Despite the return of food intake to control levels, body weight and the peripheral fat mass remained significantly reduced. The data demonstrate that the NPY Y5 receptor subtype plays a role in NPY-induced food intake, but also suggest that, with chronic blockade, counterregulatory mechanisms are induced to restore appetite.

Animals↗
PubMed1998

Evidence that hypothalamic neurotensin signals leptin effects on feeding behavior in normal and fat-preferring rats.

Leptin inhibits food intake when it is injected in the periphery or in the central nervous system. It is likely that its action is not only mediated by the inhibition of orexigenic peptides such as neuropeptide Y. Therefore, we characterized the pharmacological and physiological relationships of leptin with neurotensin (NT), a central feeding inhibitor. Firstly, we investigated the central interactions of leptin and NT. Intracerebro-ventricular (ICV) injection were done in normal Long-Evans rats. NT had a short lasting (30 minutes; p<0.01) inhibitory effect on spontaneous food intake measured at the beginning of the dark phase whereas the effect of ICV leptin was observed after 24 hours (p<0.001). Co-injection with leptin potentiated NT effect at 30 minutes (p<0. 001) and prolonged it for 30 additional minutes (p<0.01). In addition, NT potentiated the effect of leptin at 30 and 60 minutes (p<0.02 and p<0.001 respectively) but not at 24 hours. Secondly, we observed that NT concentrations were augmented in selective brain areas in fat-preferring rats (+ 34% for hypothalamic NT; p<0.03). This increase was observed in the parvocellular part of the paraventricular nucleus (PVNp) only and was associated with an increase in circulating leptin levels (+ 75%; p<0.003). Interestingly, plasma leptin and NT in the PVNp were strongly correlated (r=0.57; p<0.003), suggesting changes of NT processing or release in this nucleus. These results strongly suggest that the short-term anorexigenic effects of leptin in normal rats are at least partly mediated by changes in NT processing or release. They also suggest that these processes take place in the hypothalamus, most probably in the PVNp and that they might be sensitive to fat ingestion. Therefore, the neurotensin increase observed in fat-preferring rats would limit the overconsumption of energy, a physiological mechanism translated by leptin.

Animals↗
PubMed1998

Hypothalamic neuropeptide Y and plasma leptin after long-term high-fat feeding in the rat.

The ingestion of fat by rodents affects the level of neuropeptide Y (NPY) in the hypothalamus and we hypothesized that they might be linked via leptin, the adipose tissue hormone. The influence of fat intake on leptin and NPY levels was studied in rats fed on either a high-fat (HF) or a low fat diet (LF) for 5 months. Ingestion of the HF diet increased fat deposition (+48%; P < 0.01), leptinemia (+189%; P < 0.001) and reduced NPY levels in the arcuate nucleus (-35%; P < 0.01) and in the paraventricular nucleus (-22%; P < 0.01). However, although leptin levels reflected the amount of relative fat deposition (r = 0.62; P < 0.01), we found no evidence for a direct relationship between plasma leptin and NPY levels in the hypothalamus. These results suggest that the long-term effects of fat intake on NPY concentrations in the hypothalamus and plasma leptin are associated with different regulatory mechanisms.

Adipose Tissue↗
PubMed1998

The pharmacology of neuropeptide Y (NPY) receptor-mediated feeding in rats characterizes better Y5 than Y1, but not Y2 or Y4 subtypes.

Thirteen neuropeptide Y (NPY) agonists were administered intracerebroventricularly (i.c.v.) in rats (full dose-response curves) to estimate their half-effective dose (ED50) on feeding. These values were compared to their binding affinities (IC50) for rat NPY receptor subtypes Y1, Y2, Y4 and Y5 in vitro. Correlations between in vivo ED50 and in vitro IC50 were strong for the Y5 (r = 0.87; P < 0.01), weak for the Y1 (r = 0.48; P < 0.04) and non-significant for the Y2 and Y4 receptor subtypes. In vitro, h[D-Trp32]NPY was found to be a Y5-selective ligand and a full agonist in Y5-expressing cells. In vivo, it dose-dependently stimulated feeding, but failed to induce the full maximal response observed with pNPY. It did not antagonize pNPY-induced feeding and overfeeding in 24 h fasted rats. These findings demonstrate a role for the Y5, or possibly Y5 in combination with Y1, but not Y2 or Y4 receptor subtypes in feeding. No evidence was found for the existence of an additional, as yet undescribed, NPY feeding receptor.

Animals↗
PubMed1998

Neuropeptide Y Y1 receptor antisense oligodeoxynucleotides enhance food intake in energy-deprived rats.

In the literature, conflicting data on the effect of NPY Y1 antisense oligodeoxynucleotides (ODNs) on food intake have been reported, describing either an increase or a decrease in feeding in antisense-treated animals. In the present studies antisense oligodeoxynucleotides targeted to the Y1 receptor (Y1 antisense ODNs) were used to re-investigate the functional importance of this receptor subtype in vivo in the regulation of feeding in rats. We used phosphothioate-terminal protected derivatives of two ODN sequences used in previous reports. In addition, as one of these sequences was not tested in vitro, we demonstrated its efficacy in LMTK-cells transfected with the Y1 receptor subtype. In vivo, repeated intracerebroventricular (i.c.v.) injections of Y1 antisense ODNs did not affect basal food intake or the increase in food intake after i.c.v. injection of neuropeptide Y (NPY, 300 pmol). Y1 antisense ODNs given intracerebroventricularly enhanced food intake in energy-deprived rats (+175% and +60% vs. control scrambled and sense sequences, respectively after 2 h of refeeding). Analysis of the structure of feeding behaviour revealed that Y1 antisense ODNs enhanced fasting-induced food intake during the first hour of refeeding by inducing increases in meal size (+143% and +155% vs. sense and scrambled ODNs) but not meal duration. These data suggest that the NPY Y1 receptor is not directly implicated in feeding in the rat when calorie intake is normal but might be specifically activated during energy deprivation.

Animals↗
PubMed1998

Stimulation of feeding in lean but not in obese Zucker rats by a selective neuropeptide Y Y5 receptor agonist.

Obese Zucker rats are characterized by a reduced hypothalamic NPY receptor density. We tested the effects of intracerebroventricular injections of human NPY (hNPY) and [D-Trp32]NPY, a weak but selective NPY Y5 receptor agonist, on food intake in lean and obese Zucker rats. The effect of a maximal dose of hNPY (10 microg) on feeding was more pronounced in lean than in obese rats. [D-Trp32]NPY (10 microg) stimulated feeding in lean but not in obese Zucker rats. It did not affect the feeding response to hNPY, excluding the activation of an inhibitory receptor. These results are in favor of a down-regulation of the NPY 'feeding' receptor in the obese rat, which is suggested to be the Y5 subtype.

Animals↗
PubMed1998

Neuropeptide Y release in the paraventricular nucleus of Long-Evans rats treated with leptin.

Neuropeptide Y (NPY) and leptin are actually two of the most potent peptides involved in the regulation of food intake with their respective stimulatory and inhibitory actions. The infusion of each peptide has a significant influence on the mRNA expression of the other in the adipose tissue for leptin and in the arcuate nucleus of the hypothalamus for NPY. To confirm this functional interaction, we measured the in vivo release of hypothalamic neuropeptide Y in awake fasted and refed Long-Evans rats after intraperitoneal (I.P.) injection of leptin. For this purpose, we used the push-pull perfusion technique with the cannula placed above the right paraventricular nucleus. I.P. leptin significantly inhibited food intake during the two hours of food access (-50%; p < 0.02). NPY release was not modified by leptin alone. But, when food was present, it slightly but significantly increased (p < 0.03 or less) and remained at a sustained level in the leptin-treated rats whereas it decreased in the control saline-injected group (p < 0.04). Thus, leptin did not acutely regulate NPY release and other food-related factors are probably involved as mediators of its anorexigenic effects.

Animals↗
PubMed1998

Behavioral deficits in monosodium glutamate rats: specific changes in the structure of feeding behavior.

We studied the feeding rhythms and feeding patterns of adult Long-Evans rats treated with monosodium glutamate (MSG) in their early post-natal period. This treatment is known to induce neuronal degeneration in the arcuate nucleus (ARC), a major hypothalamic site implicated in the regulation of feeding. Neonatal rats were treated intraperitoneally with MSG or saline (controls) alone on the first days of life. At age of 6 months, male control and male MSG rats were placed in our automatic feeding system, and the structure of feeding behavior and diurnal feeding rhythms were analysed. On a 24 hours basis, MSG rats ate less than control rats (-24%). This hypophagia resulted from a mild diurnal hyperphagia (+6%) and a pronounced nocturnal hypophagia (-34%). This hypophagia was the main consequence of a decrease of meal size in MSG rats (-37%) and was associated with an increase in meal duration (+52%). It was also associated with a total disappearance of the two feeding peaks that normally occur at light and dark onset in the rat (-90% 2 h after dark onset and -49% 2 h before light onset). These results indicate that neonatal treatment with MSG induces important changes in feeding patterns and feeding rhythms in the adulthood. These changes might be related to the disappearance of neurotransmitters located in the arcuate nucleus.

Animals↗
PubMed1997

Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and, e in different mouse tissues.

Ob-Ra, b, and e are the major splice forms of the leptin receptor. This study was performed to map the tissue distribution and to quantify the 3 receptor isoforms by heterologous competitive Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and RNase Protection Assay (RNase PA). The mRNA of the truncated, membrane bound isoform Ob-Ra was found to be represented ubiquitously. Messenger RNA for the putative functional isoform Ob-Rb could be detected in brain, hypothalamus and in some peripheral tissues (e.g. heart, lung, lymph nodes). The highest ratio between Ob-Rb and Ob-Ra mRNA was found in the hypothalamus, where leptin probably exerts its satiety action. The fact that Ob-Rb mRNA was found in peripheral tissues could indicate possible additional functions of leptin. Transcripts for the shortest splice variant, Ob-Re, which is expected to encode a soluble form of the receptor, were detected in relatively high amounts in many tissues. The levels were comparable to those of leptin mRNA in fat tissue. It is conceivable, therefore, that Ob-Re might be secreted in sufficient amounts to act as a buffering system for freely circulating leptin.

Animals↗
PubMed1997

Dietary preferences in monosodium glutamate-lesioned rats: age-variable influence of hypothalamic neuropeptide Y.

In this study, we measured hypothalamic neuropeptide Y (NPY) and the food preference in weanling and adult monosodium glutamate (MSG)-lesioned and control rats. The MSG lesion was induced by three subcutaneous injections (4 g/kg body wt) during the first week of life of the rats. All treated and control weanling rats strongly preferred a high carbohydrate (HC) diet to a high fat (HF) diet. Adult control rats ate 60% more HF diet (P < 0.001) and 25% less HC diet (P < 0.01) than MSG-treated rats. At weaning and in adulthood, NPY concentrations in MSG-rats were markedly lower in the arcuate and paraventricular nuclei (P < 0.01 or less) than in control rats. The MSG treatment did not affect carbohydrate preference observed at weaning. It was associated with a limited development of fat appetite in adulthood. NPY could influence the dietary preferences more in adulthood, likely when all neuropeptidergic systems are mature.

Age Factors↗